The
GarsP278KY mouse was generated at Jackson several years ago, and was
characterized by the Burgess lab at that time. This mouse contains a
dominant mutation in the ubiquitously expressed housekeeping gene,
glycyl tRNA synthetase (Gars). At the time the mouse was generated, it
was already known that dominant mutations in human GARS resulted in
Charcot-Marie-Tooth Type 2D (CMT2D) peripheral neuropathy. GarsP278KY
represented the first mouse model of CMT2D. The mouse presents normally
at birth, but by 2-3 weeks of age shows reduced body weight and muscle
strength, neuromuscular junction dysfunction, peripheral axon
degeneration, and reduced nerve conduction velocity, among other
neurodegenerative phenotypes.
Studies
by the Burgess lab and others have revealed that in the mouse, the
mutation confers a toxic gain-of-function to the GARS protein. The data
set your class is working with was generated to work towards revealing
that gain of function. The data is RNA sequencing from whole spinal cord
of 3 mutant and 3 wild-type mice of both sexes (12 total samples) at a
post-disease onset time point (8 weeks of age). We are specifically
using this transcriptional data as a comparison against translational
data we are generating using another technique called ribosome-tagging.
As Charlie mentioned, at this point we believe the gain-of-function
mechanism leads to impairments in translation, but exactly how that
happens is still unclear. These data are giving us some clues, and we
are currently following up on mitochondrial dysfunction and amino acid
deprivation as possible leads.
© Copyright 2018 Department of Biology, Davidson
College, Davidson, NC 28035
Send comments, questions, and suggestions to: macampbell@davidson.edu